Appearance of HIV-related Kaposi's Sarcoma (KS) in Older HIV Patients with a High CD4 Count and a Low Viral Load

By Ronald Baker, PhD

The incidence of the malignancy known as Kaposi's sarcoma (KS), a type of skin cancer that causes disfiguring and sometimes painful lesions, has been declining among HIV patients since the introduction of HAART (highly active antiretroviral therapy) [1].

However, in a letter to the editor in the New England Journal of Medicine (September 27, 2007), doctors at the University of California at San Francisco (UCSF) report on a cluster of unusual cases of persistent cutaneous KS among 9 HIV patients with sustained CD4 cells counts above 300 cells/mm3 and viral load below 300 copies/mL for at least 3 years.

Profile of 9 HIV Patients with KS in San Francisco

According to the report by the UCSF doctors, all of these patients were receiving HAART regimens with at least 1 protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI).

The median age of the patients was 52 years (range 41 to 74), while the median time from HIV infection was 18 years (range 4 to 25). They had been receiving HAART for a median of 7 years (range <1 to 19), and their median lowest CD4 count was 340 cells/mm3 (range 90 to 455 cells/mm3). None of the patients had previously experienced an HIV-related opportunistic infection (OI).

The authors described the patients as having "a relatively indolent [slow] course of Kaposi's sarcoma, with no eruptive lesions, visceral involvement, or other AIDS-defining illnesses."

Kaposi's sarcoma lesion on the foot

Kaposi's sarcoma on the thigh

Kaposi's sarcoma - lesion on the foot Kaposi's sarcoma on the back Kaposi's sarcoma - close-up Kaposi's sarcoma on the thigh Kaposi's sarcoma - perianal

Concerns Raised by the San Francisco Cluster

This report of persistent HIV-related KS in patients with adequate viral suppression and relatively good immune function raises concern for several reasons, say the authors.

First, while there have been similar reports elsewhere [2], it may be that there are more such patients than previously recognized due to the large number of older individuals who are coinfected with HIV and human herpesvirus 8 (HHV-8), which is believed to be the cause of KS. If so, then questions arise about the ability of the immune systems of aging HIV patients to adequately suppress certain viruses [3].

Second, it has been argued that PI-based HAART regimens are preferable in the treatment of KS patients due to their anti-tumor and antiangiogenic effects. However, in the current case report, 7 of the patients were receiving PIs but did not experience any improvement in their KS.

Finally, these patients represent an as yet unexplained problem, because they have developed persistent KS despite receiving maximal antiretroviral therapy.

In conclusion, the authors of the letter wrote, "This phenomenon may increase in frequency as the HIV-infected population ages, and we recommend that physicians monitor this group carefully."

Information about KS from the American Cancer Society

Kaposi's sarcoma is caused by a virus called Kaposi sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus 8 (HHV-8). HHV-8 is a herpesvirus similar to the viruses that cause cold sores and genital herpes, as well as Epstein-Barr virus (which causes mononucleosis) and cytomegalovirus (CMV).

The percentage of people in the United States infected with HHV-8 is not known. Studies have found infection rates ranging from 3.5% to 25% in reports from different parts of the country. In Africa, this number is over 50% in certain areas. Most people infected with HHV-8 are not HIV positive and do not get KS. A very small number will get endemic, low-grade KS. But people who are immunosuppressed, such as those with AIDS, develop KS much more readily if they are infected with HHV-8.

Transmission of HHV-8

Apparently, the 3 major routes of HHV-8 transmission are oral (i.e., the virus infects oral epithelial cells; infection was associated with deep kissing in 1 study), semen (HHV-8 is less frequently detected in semen than in saliva), and through blood, for example via by sharing needles.

Patients should be counseled that deep kissing and sexual intercourse with persons who have high risk for being infected with HHV-8 (e.g., persons who have KS or who are HIV positive) might lead to acquisition of HHV-8.

More about Kaposi's Sarcoma

A sarcoma is a cancer that develops in connective tissues such as cartilage, bone, fat, muscle, blood vessels, or fibrous tissues related to tendons or ligaments.

For decades KS was considered a rare disease that mostly affected elderly men of Mediterranean or Jewish heritage, organ transplant recipients, or young adult African men. This type is called classic Kaposi's sarcoma. In the past 20 years, however, most KS cases have developed in association with HIV infection and AIDS, especially among gay men. This is called AIDS-related Kaposi's sarcoma.

With the introduction of HAART to treat HIV/AIDS and greater awareness of how HIV infection is acquired, the number of AIDS-related KS cases has decreased by about 85% to 90%. For example, in the Seattle area, the number of people diagnosed with Kaposi's sarcoma fell from 366 in the early 1990s to 40 in more recent years.

The disease typically causes tumors to develop in the tissues below the skin surface, or in the mucous membranes of the mouth, nose, or anus. These lesions (abnormal tissue areas) appear as raised blotches or lumps that may be purple, brown, or red. Sometimes the disease causes painful swelling, especially in the legs, groin area, or the skin around the eyes.

Although the skin lesions of KS may be disfiguring, they usually are not life-threatening or disabling. In most cases, the lesions cause no clinical symptoms. However, in some individuals, the lesions may be painful, especially if they cause swelling of nearby unaffected skin. KS does become life-threatening when it affects internal organs such as the lungs, liver, or gastrointestinal tract, which can cause major clinical symptoms. KS in the gastrointestinal tract, for example, can produce bleeding, while tumors in the lungs may cause difficulty breathing.

There are several types of KS. They all differ in patterns of symptoms and organs likely to be affected, how aggressively the cancer grows and spreads, risk factors, and other personal characteristics of patients. The treatments used and the effect on the patient's survival depend on the type of KS, as well as other factors.

"Classic" Kaposi's Sarcoma

Classic KS was first described in Jewish men of Eastern European origin or men of Mediterranean heritage (primarily Italian) between the ages of 50 and 70. Classic KS is quite rare, even in these ethnic and age groups. In the past, 10 to 15 men were affected for every woman with classic KS.

But even in the pre-AIDS era, women were starting to be affected more often, and now the ratio is closer to 4 men for every 1 woman. In classic KS, patients typically have 1 or more lesions on the hands, arms and legs, ankles, or soles of the feet. The lesions slowly get grow and new lesions may develop over the course of 10 to 15 years. Pressure from the lesions can block lymph vessels, causing swelling that may be painful. Lesions can also develop in the gastrointestinal tract, lymph nodes, and elsewhere in the body, although they rarely cause symptoms.

African (Endemic) Kaposi's Sarcoma

African (or endemic) KS is a form of the disease that develops in people living in Equatorial Africa, where the disease is fairly common. It accounts for 9% of all the cancers seen among Ugandan men, for example. In many cases, this disease is identical to classic KS, although it usually develops at a much younger age and affects many more men than women.

Typically, African (endemic) KS causes skin lesions that do not produce clinical symptoms and do not spread to other parts of the body. However, more aggressive cases do occur, and some skin tumors may penetrate the underlying bone. Another form of the disease strikes children before puberty, affecting 3 times as many boys as girls, and usually involves the lymph nodes and other organs. In most cases, it leads to death within 3 years.

Transplant-related (Acquired) Kaposi's Sarcoma

Transplant-related (or acquired) KS develops in people whose immune systems have been suppressed after an organ transplant. Usually a transplant patient must take drugs to prevent the immune system from rejecting the newly transplanted organ. Because these drugs weaken the body's defenses, oportunistic diseases or infections can take hold.

Kaposi's sarcoma is 150 to 200 times more likely to develop in transplant recipients than in the general population. Often, transplant-related KS affects only the skin, but in some cases the disease can spread to the mucous membranes or other organs.

AIDS-related (Epidemic) Kaposi's Sarcoma

AIDS-related (or epidemic) KS develops in people who are infected with HIV. Early in the HIV/AIDS epidemic in the U.S., doctors began to see an unusual and sudden appearance of this form of KS, which led them to theorize that a new, epidemic disease had emerged.

HIV destroys certain cells of the immune system, rendering it unable to fight infections caused by certain other viruses, bacteria, and parasites. Certain cancers are also more likely to develop in people whose immune systems have been damaged.

A person infected with HIV does not necessarily have AIDS. The virus can be present in the body for a long time -- typically many years -- before causing any major illness. AIDS develops when the virus has seriously damaged the immune system, rendering a person susceptible to certain types of opportunistic infections and other complications.

Certain diseases occur so often in people with AIDS that they are considered AIDS-defining conditions -- that is, their presence in a person infected with HIV is a clear sign that full-blown AIDS has developed. The Centers for Disease Control and Prevention (CDC) has identified certain cancers as AIDS-defining illnesses: KS, lymphoma (especially non-Hodgkin lymphoma and primary central nervous system lymphoma), anal cancer, and invasive cervical cancer.

Many other kinds of cancer may be more likely to develop in people who are HIV-positive. Of course, people without HIV or AIDS can also have these types of cancer.

In most cases, epidemic KS causes widespread lesions that erupt at many places on the body soon after AIDS develops. Lesions of epidemic KS may develop on the skin and in the mouth, and may affect the lymph nodes and other organs, usually the gastrointestinal tract, lung, liver, and spleen.

In contrast, classic KS usually affects only 1 or a few areas of skin, most often the lower legs. When they are diagnosed, however, some people with epidemic KS have no symptoms, especially if their lesions only develop on the skin. However, many -- even those with no skin lesions -- have swollen lymph nodes, unexplained fever, or weight loss.

Eventually, in almost all patients, epidemic KS spreads throughout the body. Extensive lung involvement can be fatal. This is uncommon today among people receiving medical treatment, because HAART and anti-KS drugs usually prevent advanced Kaposi's sarcoma from spreading.

Prevention and Treatment of HIV-related KS

Lower rates of KS have been observed among AIDS patients treated with ganciclovir (Cytovene) or foscarnet (Foscavir) for CMV retinitis, according to the Guidelines for the Prevention of Opportunistic Infections among HIV-Infected Persons -- Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America [4].

HHV-8 replication in vitro is inhibited by ganciclovir, foscarnet, and cidofovir (Vistide). However, because the efficacy and clinical use of these drugs in preventing KS have not been established, no recommendation can be made concerning use of these or other drugs to prevent KS among persons coinfected with HIV and HHV-8.

According to the U.S. Public Service guidelines, "potent antiretroviral drug combinations that suppress HIV replication reduce the frequency of KS among HIV-infected persons…and should be considered for all persons who qualify for such therapy."

Following is the text on treatment of HHV-8 from the Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America.

"Although ganciclovir, foscarnet, and cidofovir have in vitro activity against HHV-8, and limited studies indicate these agents might be associated with reduced disease progression or lesion regression, larger and more definitive studies are needed to determine whether antiviral therapy has a useful role in managing HHV-8-associated diseases. Potent [antiretroviral therapy] that suppresses HIV-1 replication reduces the frequency of occurrence of Kaposi sarcoma among HIV-1-infected persons and should be considered for all persons who qualify for such therapy." [5]

For comprehensive coverage of treatment options for HIV-related Kaposi's sarcoma, see Treatment of HIV-associated Kaposi Sarcoma by JH Von Roenn, MD, of Northwestern University, which is published in the HIV InSite Knowledge Base (from UCSF's HIVInsite web site). [6]

Treatments covered in Dr. Von Roenn's review include local therapies (radiation therapy, intralesional chemotherapy, cryotherapy, topical retinoids, and systemic therapies (interferon, cytotoxic chemotherapy, single agent chemotherapy, and combination chemotherapy regimens, as well as investigational therapy.

10/02/07

Source

T Maurer, M Ponte and L Kieron. HIV-Associated Kaposi's Sarcoma with a High CD4 Count and a Low Viral Load. New England Journal of Medicine 357: 1352-1353. September 27, 2007.

References

1. JH Gallafent, SE Buskin, PB De Turk, and others. Profile of patients with Kaposi's sarcoma in the era of highly active antiretroviral therapy. Journal of Clinical Oncology 23: 1253-1260. 2005. [Free Full Text]

2. J Chan, S Kravcik and JB Angel. Development of Kaposi's sarcoma despite sustained suppression of HIV plasma viremia. Journal of Acquired Immune Deficiency Syndromes 22: 209-210. 1999.

3. A Guihot, N Dupin, AG Marcelin, and others. Low T cell responses to human herpesvirus 8 in patients with AIDS-related and classic Kaposi sarcoma. Journal of Infectious Diseases 194: 1078-1088. 2006.

4. Guidelines for the Prevention of Opportunistic Infections among HIV-Infected Persons-- Recommendations of the U.S. Public Health Service and the Infectious Diseases Society of America. June 14, 2002.


5. Treating Opportunistic Infections among HIV-Infected Adults and Adolescents-Recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. December 17, 2004.

6. JH Von Roenn. Treatment of HIV-associated Kaposi Sarcoma. June 2003.